The gamma-(N)-heterocyclic carboxaldehyde thiosemicarbazones represent the most potent of the known inhibitors of ribonucleoside diphosphate reductase. This project will involve the design and synthesis of a derivative of this class with high affinity for the reductase enzyme which is not susceptible to enzymatic degradation by o- glucuronide formation. Bioreductive alkylating agents of the benzo- and naphthoquinone class will be fabricated in an effort to develop a water-soluble derivative which can be formulated for clinical utility in man. The role of particulate alkaline phosphatase in the acquisition of insensitivity to the 6-thiopurines by transplantable neoplastic cells and those of acute lymphocytic leukemia will be investigated. Derivatives of gamma-(N)-heterocyclic carboxaldehyde thiosemicarbazones and tetramisole will be studied in an effort to develop an inhibitor of alkaline phosphatase which may be employed in combination with the 6-thiopurines to restore sensitivity to these agents.